This proposal describes a 5 year plan for mentored clinical and laboratory training designed to prepare the candidate to an independent academic career as a physician-scientist. The applicant is an MD, PhD, who recently completed the 4 year residency program in Medical Genetics at Baylor College of Medicine. The career development plan includes mentored research training which will include: i) regular meetings with the mentor, ii) biannual meetings with a Scientific Advisory Committee iii) didactic courses, iv) seminars, v) lab meetings, vi) national meetings, and vii) international meetings. The training will take place at Baylor College of Medicine providing an excellent training environment with access to the latest tools of genome study. The project main aim is to elucidate the biology of the human peripheral nerve in health and disease through the identification of novel genes implicated in Charcot-Marie-Tooth (CMT) disease. CMT is a progressive neurological disease caused by deterioration of the peripheral nerves with secondary muscle wasting and weakness. The disease is extremely heterogeneous both clinically and molecularly. We will study a cohort of well described patients with hereditary peripheral neuropathy and no obvious disease-causing sequence variants in any of the 32 known CMT genes. The genomic profile, including copy number variations and single nucleotide variations will be determined for index patients with the application of state of the art molecular techniques (next generation sequencing and genomic microarrays). Genomic data, after bioinformatics processing and filtering, will be mined to identify candidate genes. The methods of conventional genetics, molecular biology, and bioinformatics will be implemented to further validate the disease-causing potential of novel candidates PUBLIC HEALTH RELEVANCE: The project main aim is to elucidate the biology of the human peripheral nerve in health and disease through the identification of novel genes implicated in Charcot-Marie-Tooth disease (CMT). This proposal focuses on using state of the art genome sequencing, and array comparative genomic hybridization to systematically assess genetic variants in selected patients with CMT neuropathies.